Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity and antimicrobial activity

Abstract

Fluoroquinolones are potent inhibitors of bacterial topoisomerase II (DNA gyrase). They can also inhibit eukaryotic topoisomerases, which could possibly lead to clastogenicity and/or cellular toxicity. Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the fluoroquinolones and the potential of these compounds to induce micronuclei, a genetic toxicity endpoint. In an effort to identify potent nontoxic quinolone antibacterials, we have examined the structural features of the fluoroquinolones associated with mammalian cell cytotoxicity. An investigation of a wide variety of substituents at the 1, 5, 7, and 8 positions of a quinolone nucleus was conducted. The results indicate that no one position has a controlling effect on the observed cytotoxicity. Instead, a combination of the various substituents contributes to the effects seen. Certain trends were apparent, such as the fact that compounds with pyrrolidines at the R-7 position were more cytotoxic than those with piperazines, and halogens at R-8 (X-position) were associated with more cytotoxicity relative to hydrogen. A general trend also existed between the cytotoxicity of the compounds and their Gram-positive antibacterial activity. A detailed comparison between the various groups and positional variations as they controlled the cytotoxicity and antibacterial activity is presented.

Comparative genotoxicity of quinolone and quinolonyl-lactam antibacterials in the in vitro micronucleus assay in Chinese hamster ovary cells

“…Quinolones are a class of antibacterial agents structurDifferences in substituted moieties can greatly affect ally related to nalidixic acid, a 1,8-naphthyridine-3-car-both the bactericidal activity and toxicity of quinolones boxylic acid. The antibacterial activity of quinolones is [Suto et al, 1992;Domagala, 1994]. With this in mind, due to their ability to inhibit bacterial DNA gyrase [von much research has been directed at modifying quinolones Rosentiel and Adam, 1994] yet their cross-reactivity with to achieve improved antibacterial spectrum, reduced demammalian topoisomerase II leads to undesired toxicity velopment of resistance, and reduced toxicity to humans.…”

Drug features that contribute to the activity of quinolones against mammalian topoisomerase II and cultured cells: correlation between enhancement of enzyme-mediated DNA cleavage in vitro and cytotoxic potential

“…1) and CP-67,015, also were reported to stimulate DNA cleavage mediated by the eukaryotic type II enzyme (3). Since that initial report, a number of novel quinolones with activity against topoisomerase II, eukaryotic cells, or mammalian tumors have been described (8,9,18,19,31,32,37,(39)(40)(41). In contrast to clinically relevant quinolone antimicrobial agents, many of these latter compounds contain an aromatic substituent at the C-7 position (3,9,18,31,32,39,40).…”

Pharmaceutical Potential of Synthetic and Natural Pyrrolomycins

“…Moreover, natural pyrrolomycin F3 and the synthetic analogue 20a have a very low cytotoxicity in human primary cell cultures, with a selectivity index >1000. This is remarkable if one considers that a good safety margin for a compound to be considered as a potential candidate for clinical development is a selectivity index >200 [55]. Another advantage of pyrrolomycins is related to their simple chemical synthesis, which allows us to easily obtain them although producing organisms are no longer available.…”